PROJECT SUMMARY Major Depressive Disorder (MDD) is a serious, highly prevalent illness in youth, affecting more than 12% of adolescents in the United States. Despite important advances in the treatment of depression, the majority of adolescents remain untreated, inadequately treated or cannot tolerate an adequate course of treatment. As MDD continues to pose a significant public health problem, well-tolerated new interventions are necessary. The main objective of this Phase I research program is to develop a smartphone application, CT-152a, that is effective in treating adolescent depression and addresses many of the current barriers to effective treatment, including lack of qualified mental health practitioners, perceived stigma, pharmacological side effects, and concerns about cost, accessibility, and confidentiality. CT-152a builds upon Click Therapeutics? CT-152, a new class of digital therapeutic interventions which focus on neural models of psychological dysfunction. CT-152 combines a cognitive-emotional training intervention (Emotional Faces Memory Task; EFMT) and psychotherapeutic text messaging, delivered as a mobile application on Click?s clinically-validated Neurobehavioral Intervention Platform. The Emotional Face Memory Task targets an imbalance in activity in specific regions of the brain: the limbic system (amygdala), involved in emotion processing, and PFC regions (DLPFC and VLPFC) involved in cognitive control and cognitive reappraisal of emotion. EFMT utilizes working memory and facial affect identification tasks to modulate amygdala ? prefrontal cortex connectivity, enhancing control of emotional processing information, and in adult clinical trials has shown the potential to rebalance functioning between these neural nodes and reduce MDD symptoms. The proposed project will adapt this highly innovative therapeutic intervention for use with adolescents. This will require development and testing of adolescent appropriate content to complete a CT-152a prototype. Upon successful completion of this project, we will seek rigorous clinical evidence for efficacy and safety in Phase II, necessary for successful commercialization in the digital therapeutics market. CT-152a?s innovative delivery through a smartphone has the potential to significantly expand access to treatment, offering adolescents (the vast majority of whom have smartphone access) a low cost, 24/7, confidential, evidence-based therapeutic intervention with a very favorable safety profile that can be prescribed across clinical settings, where early signs of depression are often identified.